1. Field of the Invention
The present invention relates to regimens and therapeutics intended to inhibit the formation, progression and metastatic conversion of a variety of cancers in mammals, including humans. Cancers effectively targeted by this regimen include solid tumors of a wide variety, and include primary tumors, as well as secondary cancers, such as a prostate, cancer metastasizing into bone cancer. Specific cancer targets include liver cancer, prostate cancer, breast cancer, colorectal cancer, stomach cancer, esophageal cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, ovarian cancer, uterine cancer, multiple myeloma, leukemia, lymphoma, melanoma, sarcoma, ovarian, uterine, nasopharyngeal, brain, thyroid or kidney cancer. Although the inventors have not yet had the opportunity to test this regimen against all cancer types, it does not appear restricted in its applicability to any given cancer type or line, as galectin-3 molecules are present in a great variety of tumors and the molecular synergistic effects are not tumor specific. The invention is also effective against non-solid tumors such as leukemias and lymphomas.
The regimen provided depends on an observed synergy between two documented anticancer agents, honokiol (derived from the magnolia plant originally) and modified citrus pectin, citrus pectin that is broken down either through heat, hydrolysis or enzymatic degradation to lower molecular weight and partially esterified galacturonic acid moieties. Instead of MCP which is widely available from the Assignor of this application, EcoNugenics Inc. of Santa Rosa Calif. as both Pecta-Sol® and PectaSol-C® Modified Citrus Pectin or MCP, similarly modified alginates may be employed.
2. Background of the Invention
MCP and Honokiol are both well-known non-toxic and well-tolerated agents effective in a variety of treatments. Honokiol has been used for many years in Chinese herbal therapy annals, and been shown to be effective in inhibiting platelet aggregation, protection of the myocardium against ischemic damage and exhibits anti-inflammatory, antibacterial and anti-oxidative properties. Hahm et al, Clin. Cancer Res. 14(4) (2008). Honokiol has also been demonstrated to be an effective anti-cancer agent. It has been shown to induce apoptosis in lung cancer cells, Yeng et al, Biochem. Pharmacol. 63:1641-51 (2002) probably through caspase activation, and been shown to be effective in vivo against colorectal cancer and breast cancer in nude mice bearing transplanted tumors. Wang et al, World J. Gastoenterol. 10:3459-63 (2004).
Independent of mechanistic explanations, Honokiol has been shown to inhibit the formation of cancer cells, inhibit the progression of cancer cells and target cancer cells for destruction through apoptosis and inhibit spontaneous metastases of established cancer cells. This has been demonstrated in vitro against cancer cell lines, and in vivo in mammals including rodents and humans. Importantly, promising effects against cell lines have been repeatedly demonstrated to be echoed in in vivo testing. Shigemura et al, Cancer: 109(7) 1279-89 (2007) and Bai, et al, J. Biol. Chem.: 278, 35501-7, (2003) and Ahn et al, Mol. Cancer. Res.: 4(9) 621-32 (2006). Honokiol is widely available, and can be obtained from Herbal Extracts Plus of Croyden, Pa. and Century Supplements of Vancouver, British Columbia, as well as a large number of herbal supplement providers. It is non-toxic and well tolerated, and has effectiveness, in various indications, at values of 2-500 mg/kg/day, with optimum values for anti-cancer applications in the range of 25-150 mg/kg/day.
Modified Citrus Pectin (MCP) and its corresponding alginate derivatives, polysaccharides having a molecular weight of less than 40,000 daltons, are well established as therapeutic agents. U.S. Pat. No. 7,026,302 as well as related U.S. Pat. Nos. 6,462,029 and 6,274,566 describe MCP products and alginates prepared by either hydrolysis or enzymatic digestion shown to be effective in treatment of a wide variety of poisoning and disease states. The disclosure of these patents is incorporated herein-by-reference. U.S. Pat. No. 7,451,871 also discloses the use of these modified citrus pectins and related compounds having a low enough molecular weight to be easily absorbed and having partially esterified galacturonic acid moieties as aids in controlling cancer metastases by binding the cancer emboli in the blood stream. Both the '871 patent, and U.S. patent application Ser. No. 11/485,955, which discloses that MCP can be used to enhance the immune system response of mammals, are incorporated herein-by-reference.
The antineoplastic effect of MCP is well documented. Gunning et al, FASEB J., Vo. 23, 415-424 (2009) first reviews the demonstrated effectiveness of MCP against a variety of cancers, both in terms of inhibiting progression and metastases, and establishes that these modified pectins and alginates bind in vivo, the mammalian protein galectin-3. Galectin-3 (Gal3) is a protein implicated in a number of different cancer cell progressions and metastatic conversions, and by binding this protein, the transformation of cells into cancerous cells may be inhibited, and the progression of existing cancers slowed. In addition to binding cancer emboli and suppressing metastases through these processes, MCP may also be effective in suppressing the conversion to metastatic forms. Yan and Katz, Int. Cancer Ther. 9 (2), 197-203 (2010). MCP has been shown to be effective in the treatment of, and inhibition of, prostate cancer, Pienta et al, J. Natl. Cancer Inst., 24, 1854-62 (2002) as well as lung cancer, fibrosarcoma and melanoma. Kay et al, Am. J. Clin. Nutr., 30, 171-175 (1997) as well as other solid tumors, such as breast cancer, liver cancer and colorectal cancer. MCP appears to bind to Gal3 present on the surface of tumor cells, both solid and non-solid, which inhibits those tumors from developing or transforming. Azemar et al, Oncology, 1, 73-80 (2007). The immunomodulating effect of MCP may be due to a similar phenomenon, where binding triggers certain chemical releases or inhibits inflammation, cell adhesion and cell migration. Id.
Accordingly, those of skill in the art are aware of two well tolerated, non-toxic agents, honokiol and MCP, both substances commercially available in high levels of purity, that are effective as anti-cancer agents. They are administrable over a wide variety of protocols, including IM and IV and parentaral administration, as well as subcutaneous administration and by adsorption through mucosal membranes, desirably through rectal and vaginal suppositories. Perhaps most importantly, they have been shown to be effective as orally administered, and may be taken daily, in one dose or in multiple doses per day, as part of a dietary regimen. They have been demonstrated to be safe and effective over a wide range of dosages, with honokiol being shown as effective over 10-500 mg/kg/day, and MCP at levels of 15-700 mg/kg/day (1-50 g/day), with an optimum level, for exhibiting effectiveness against cancer, at about 75-300 mg/kg/day (5-20 g/day.)
Neither of these agents is completely effective on its own against particularly intractable cancers, such as liver and colorectal cancer cells. Honokiol has been administered with low-dose docetaxel (to avoid systemic effects). The combination gave, to a limited degree, an additive effect improving the effectiveness over the administration of honokiol alone, but not a substantial improvement over conventional chemotherapeutic administration. Shigemura et al, p. 1280. As noted in the art, even securing additive effects for the administration of two agents directed against the same cancer or cancers is rare. Typically, only the impact of the more effective of two drugs is observed, with little improvement secured where both drugs are administered at therapeutic effective levels. What is frequently desired, but rarely observed, is a synergistic combination of two agents administered against a common target or disease condition. By definition, such synergy is unpredictable. Those of skill in the art continue to search for such a combination to combat the transformation of cells into cancerous cells, the progression of these cancers, and the transformation of those cancers to metastatic cancers.